Antibody to Protein C has been found to act in conjunction with tumor necrosis factor ("TNF") to cause tumor cell death, as described in U.S. Pat. No. 5,147,638. In contrast, treatment with TNF alone or antibody to Protein C alone is markedly less effective in the treatment of cancer. A possible explanation for the increased efficacy of combined antibody to Protein C and TNF may be that TNF induces or augments the expression of tissue factor ("TF") by tumor cells or non-tumor cells such as infiltrating white blood cells or endothelial cells associated with the tumor vasculature, or induces necrosis of the tumor cells and, thus, the release of TF from the dying cells. The TF expressed or released then may initiate clotting within the tumor associated vasculature.
Protein C is an endogenous plasma protein that normally acts as a systemic anticoagulant by cleaving clotting factors, such as Factor VIII:C and Factor V. Treatment with antibody to Protein C inhibits the anti-coagulant activity of Protein C. Thus, in conjunction with agents that induce or augment tumor TF expression or release, anti-Protein C antibody may initiate or facilitate clotting within the tumor associated vasculature, compromising the blood supply to the tumor, leading ultimately to tumor cell death. Administration of antibodies to Protein C, however, may be problematic because of the likelihood of systemic thrombosis as a serious side effect. TFPI is an endogenous, systemically circulating plasma protein which functions as a physiological anticoagulant by inhibiting TF/Factor VIIa complexes and preventing them from activating the extrinsic pathway of coagulation. Cellular TF expression occurs generally only under pathological conditions, including but not limited to, for example, vasculature disruption, wounds, malignancy, sepsis, and other conditions. Regulation of TFPI, therefore, may be an important mechanism for regulating the amount of TF-mediated coagulation in these pathological conditions.
TFPI also acts to inhibit what is known in the art as "the common pathway of coagulation" by inhibiting Factor Xa. TFPI is therefore also probably important in regulating the amount of Xa-mediated coagulation in situations in which Xa formation might occur independently of TF/Factor VIIa activation, for example, as in the case of certain mucinous adenocarcinomas that possess proteins capable of directly activating Factor X to Factor Xa.
With regard to a treatment for cancer, therefore, it would be desirable if thrombosis can be induced locally or can be targeted to a particular region, for example, specifically to tumor tissues so as to avoid generalized thrombosis.